ATM localization and heterochromatin repair depend on direct interaction of the 53BP1-BRCT2 domain with γH2AX

Robert A. Baldock, Matthew Day, Oliver J. Wilkinson, Ross Cloney, Penelope A. Jeggo, Antony W. Oliver, Felicity Z. Watts, Laurence H. Pearl

Research output: Contribution to journalArticlepeer-review

Abstract

53BP1 plays multiple roles in mammalian DNA damage repair, mediating pathway choice and facilitating DNA double-strand break repair in heterochromatin. Although it possesses a C-terminal BRCT2 domain, commonly involved in phospho-peptide binding in other proteins, initial recruitment of 53BP1 to sites of DNA damage depends on interaction with histone post-translational modifications--H4K20me2 and H2AK13/K15ub--downstream of the early γH2AX phosphorylation mark of DNA damage. We now show that, contrary to current models, the 53BP1-BRCT2 domain binds γH2AX directly, providing a third post-translational mark regulating 53BP1 function. We find that the interaction of 53BP1 with γH2AX is required for sustaining the 53BP1-dependent focal concentration of activated ATM that facilitates repair of DNA double-strand breaks in heterochromatin in G1.

Original languageEnglish
Pages (from-to)2081-2089
Number of pages9
JournalCell Reports
Volume13
Issue number10
DOIs
Publication statusPublished - 15 Dec 2015

Keywords

  • animals
  • ataxia telangiectasia mutated proteins/metabolism
  • chromosomal proteins, non-histone/metabolism
  • crystallography, X-Ray
  • DNA breaks, double-stranded
  • DNA repair/physiology
  • DNA-binding proteins/metabolism
  • fluorescent antibody technique
  • gene knockdown techniques
  • heterochromatin/metabolism
  • histones/metabolism
  • humans
  • Intracellular Signaling Peptides and Proteins/metabolism
  • mice
  • protein processing, post-translational
  • protein structure, quaternary
  • RNA, small interfering
  • transfection
  • tumor suppressor p53-binding protein 1

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